The long-term goal of this research is to understand the roles of neuroendocrine peptides in normal development and homeostasis. Several lines of evidence suggest that th4e CRF system including CRF and its related molecule UCN and their receptors (CRFR1 and CRFR2) play essential role in thee processes. Deviation of regulated activity of this system is implicated in a variety of affective disorders. Components of this system are also expressed in developing tissues. The objective of this proposal is to clarify development and physiological role of individual components of this system by employing gene-targeting method to generate mice carrying mutations in each component of the CRF system. Furthermore, generation of mice deficient in more than one component of this system will provide opportunity to dissect out molecular and cellular and neural complexity of this system. The aims are: Specific Aim 1: To determine the roles of CRFR1, CRFR2, UCN, and CRF in functioning of the HPA axis and the sensitivity of this axis to stress by examination of CRFR1, CRFR2, CRFR1/CRFR2, UCN, and CRF mutant mice under stress. Specific Aim 2. To determine the physiologic roles of CRFR2 and UCN in vascular development and function. Specific Aim 3. To determine the roles of CRFR1, CRFR2, UCN, and CRF in normal hair cycle and skin development and their role sin local stress responses by analyzing their altered state in the CRFR1, CRFR2 CRFR1/R2, UCN, and CRF mutant mice. Specific Aim 4. To determine the roles of CRFR1 and CRFR2 in the sympathetic nervous system by examining the expression of CRFR1, CRFR2, UCN, and CRF in the sympathetic ganglia and their target tissues and the effects of the absence of these receptors and ligands in mutant mice on sympathetic tone.